Lecture 12: Treatments for Diarrhea, Abdominal Pain, and Constipation Flashcards
What are the 3 Opioid Agonists used to treat diarrhea?
- Loperamide
- Diphenoxylate
- Eluxadoline
What is the MOA of Loperamide as an Anti-diarrheal?
- Interferes w/ peristalsis (slows transit time)
- Direct action on circular and longitudinal ms. of intestinal wall
What is one of the serious side-effects related to Loperamide?
Cardiac toxicities leading to death
Which anti-diarrheal agent is given with a small amount of atropine to discourage abuse/OD’s?
Diphenoxylate (opioid agonist)
MOA of Diphenoxylate?
- Exerts effects locally and centrally on GI smooth muscle cells
- Inhibits GI motility
- Slow excess GI propulsion
What is the MOA of the anti-diarrheal Eluxadoline?
- Agonist at opioid mu and kappareceptors inGI tract –> slows peristalsis/delays digestion
- Antagonist at delta opioid receptors in GI –> ↓ stomach, pancreas and biliary secretion
Eluxadoline (opioid agonist) is indicated for use in which patients?
IBS-D (diarrhea predominant subtype)
What is the the most serious adverse effect associated with Eluxadoline?
Which patients are most at risk?
- Hepatic/pancreatic toxicity
- Pancreatitis = high-risk in pts w/o GB –> DEATHs have occurred
The anti-diarrheal, Eluxadoline, is contraindicated in which 5 conditions?
1) Biliary duct obstruction
2) Sphincter of Oddi dysfunction
3) Alcoholism
4) Hx of Pancreatitis
5) Severe hepatic impairment
Therapy with the anti-diarrheal, Eluxadoline, should be stopped if what develops?
Severe constipation develops and lasts 4+ days
What is the 5-HT3 antagonist used as an anti-diarrheal?
Alosetron
What is the only indication for using the antidiarrheal, Alosetron?
Chronic, severe IBS-D that is NOT responsive to other conventional therapies
What is a major adverse effect related to the anti-diarrheal, Alosetron?
If which side effect develops should therapy be stopped?
- Ischemic colitis (black box warning!)
- Constipation is an adverse effect and if this occurs, STOP THERAPY!
What are the regulations for prescribing the anti-diarrheal, Alosetron due to one of its severe adverse effects?
i.e., what must both the doc and pt do
- No refills w/o a follow up exam!
- Doc must enroll in prescribing program
- Doc and pt must sign a risk-benefit statement and agree to adhere to therapy plans
- Additional self-training and testing by Docs to learn to appropriately Dx IBS required!
What are the contraindications for the anti-diarrheal, Alestron?
Hx of Active:
- GI obstruction, perforation, stricture, adhesion or toxic megacolon
- Diverticulitis, Chron Dz, or UC
- Impaired intestinal circulation, thrombophlebitis or a hypercoagulable state
What is the Cl- Channel Inhibitor used as an Anti-diarrheal?
Crofelemer
What is the MOA of the anti-diarrheal, Crofelemer?
- Inhibits Cl- secretion by blocking:
- cAMP-stimulated CFTR channels and
- Calcium-activated (CaCC) chloride channels
What is the specific indication for using the anti-diarrheal, Crofelemer?
Non-infectious diarrhea in HIV/AIDS pts. on anti-retroviral tx
Which drug class is used for abdominal pain/spasms associated with IBS?
Anti-muscarinics
What are the 4 antimuscarinics used for abdominal pain/spasms associated w/ IBS?
- Hyoscyamine
- Dicyclomine
- Clindinium/Chlordiazepoxide
What is the guanylate cyclase-c agonist used for constipation and it’s two MOA?
- Linaclotide
- Binds GC-C on luminal surface of intestinal epithelium and increases intra/extracellular [cGMP]
- Stimulates secretion of Cl-/HCO3- into intestinal lumen via activation of CFTR ion channels
What are the indication for use of the anti-constipation agent, Linaclotide?
- Constipation predominant IBS (IBS-C)
- Chronic idiopathic constipation (CIC)
What is the Selective Chloride (C2) Channel Activator used for treatment of constipation?
Lubiprostone
*“Lubi“-prostone –> “Lubes up the GI”
What is the MOA for the anti-constipation drug, Lubiprostone?
- A bicyclic FA, PGE-1 derivative
- Increases intestinal fluid secretion by activating GI specific chloride channels (CIC-2) in luminal cells of intestinal epithelium
What are the 3 specific indications for the use of the anti-constipation agent, Lubiprostone?
- Constipation predominant IBS (IBS-C)
- Chronic idiopathic constipation (CIC)
- Opioid-induced constipation (OIC) –> chronic pain, NON-cancer/past cancer adults*****
What are the 3 peripheral opioid antagonists used for constipation?
- Methylnaltrexone
- Naloxegol
- Alvimopan
What is the MOA for the peripheral opioid antagonists used for constipation?
Antagonists at peripheral mu-opioid receptors
What is the specific indication for the 3 peripheral opioid receptor antagonists used for constipation?
- Opioid-induced constipation (OIC) –> chronic pain, non-cancer/past cancer adults –> Methylnaltrexone and Alvimopan
- Alvimopan = hospital use ONLY –> for accelerating time to GI recovery following bowel resection surgery (prevention of postoperative ileus)
Which peripheral opioid antagonist is for hospital use only and is used to accelerate time to GI recovery post-surgery and for prevention of post-op ileus?
Alvimopan
Which anti-constipation agent carries a risk of MI with use?
Because of this what is the restriction on its use?
- Alvimopan
- REMS program requires use only in approved facility for max of 15 doses
What are the 5 laxative/cathartic agents used that are bulk forming agents?
- Dietary fiber/bran
- Psyllium
- Methylcellulose/Carboxymethylcellulose
- Calcium polycarbophil
How many days does it take to see the efficacy of the bulkforming laxative agents?
2-4 days
Are there drug-drug interactions with the bulk forming agents, if so which ones specifically?
What is recommended for dosing these agents?
- LOTS! —> Mainly w/ psyllium and the celluloses
- Recommendation similar to antacids, take 2 hours after other meds
Which 2 agents belong to the stool softener category?
1) Docusate ‘salts’
2) Mineral oil
Stool softening agents are also known as what kind of laxatives?
- Surfactant or Emollient laxatives
How do stool softeners work?
- Anionic surfactants = soften/lubricate feces by reducing surface tension
- Mineral oil is hydrocarbon-based, is indigstible and penetrates stool thereby softening it
When is the efficacy of Stool Softeners seen (i.e., how many days)?
- In 1-3 days
- Minimal laxative effect; softening mainly
Which 5 agents belong to the stimulant class of laxatives/cathartic agents?
- Bisacodyl
- Castor oil
- Glycerin
- Senna
- Sodium Picosulfate
What is the MOA of the stimulant class of laxatives?
- Irritant to enterocytes, GI smooth m. –> inflammation
- Na+/K+- ATPase inhibition and/or increase in prostaglandin synthesis/secretion (via cAMP/cGMP)
- Promote water/electrolyte accumulation in GI
Castor oil, part of the stimulant class of laxatives is hydrolyzed into what?
Ricinoleic acid —> promotes H2O/electrolyte accumulation in GI
Which laxative agent is associated with urine discoloration (yellow-brown/red-pink)?
Senna (stimulant class)
Sodium picosulfate (stimulant) contains magnesium oxide/anhydrous citric acid and is converted into?
Magnesium citrate (osmotic)
What is the efficacy of the stimulant class of laxatives (i.e., how long to work)?
Which agent in the class has soonest onset?
- Usually 12-36 hours
- Sooner w/ glycerin
What are the contraindications and cautions for the use of the stimulant class of laxatives?
- Contraindications = GI obstruction, Ileus, or impaction (don’t want to irritate bowel in these pts!)
- Caution = several of these agents pass into breast milk
Which laxative agents are given the evening before colonscopy?
- Sodium Picosulfate (stimulant)
- Large dose of PEG-3350 = Osmotic
What are the 2 agents in the saline class of laxatives?
1) Magnesium salts
2) Sodium phosphate
What drug interactions must be accounted for when using Saline Agents as laxatives?
Diuretics (electrolyte balance)
Caution must be taken when using Saline Agents as laxatives in patients with which conditions?
- Renal disease (electrolytes)
- CHF/HTN (sodium)
What are the 4 agents part of the Osmotic class of laxatives?
- Lactulose
- Magnesium Citrate
- Sorbitol
- PEG-3350
What is the MOA of the laxative, Sorbitol?
Non-absorbably sugar hydrolyzed to SCFA’s retaining fluid in GI (increased motility)
Which osmotic agent is also used for severe liver disease patients w/ hyperammonemia?
Why?
- Lactulose
- Change in pH traps ammonia in the GI!
Adverse effects with osmotic agents used as laxatives?
- Electrolyte disturbances; watch closely
- Abdominal pain/distention/flatulence
What is polyethylene glycol (PEG-3350) used for?
- Large doses for bowel prep prior to GI scopes, radiological procedures or surgery
- Small doses for constipation
What is the efficacy of large doses vs. smaller doses of osmotic agents as laxatives?
- Large doses = 1-3 hours
- Smaller doses = 0.5 to 3 days
Which laxative/cathartic agent is a tri-hydroxyl alcohol that functions as an irritant (stimulant), osmotic, and lubricant agent?
Glycerin
